Stem Cell Week, Sept 23, 2002 p4
Bone marrow donor cells present in muscle fibers of boy with MD years after transplant
Full Text: COPYRIGHT 2002 NewsRX
2002 SEP 23 - (NewsRx.com & NewsRx.net) -- Researchers have found that donor cells from a bone
marrow transplant given to a 1-year-old boy later diagnosed with muscular dystrophy remained in the
patient's muscle 13 years later.
The findings, by researchers at Children's Hospital Boston and Children'sHospital Los Angeles, suggest
that human bone marrow cells can become part of diseased muscle fibers and be detected many years
after transplantation.
The new results, reported in the September 2002 issue of the Journal of Clinical Investigation, come from
a patient who suffers from two serious genetic diseases. When he was 6 months old, doctors at Children's
Hospital Los Angeles diagnosed this patient with X-linked severe combined immune deficiency (SCID).
Often known as "bubble boy disease" after David Vetter, the patient who lived in a germ-free plastic
bubble for 12 years, SCID results from a genetic mutation that greatly reduces the body's ability to fight
off disease. Patients have little resistance to infections such as pneumonia and meningitis, which can
therefore be life threatening.
Roughly one in 100,000 newborns have one of the several forms of SCID. The X-linked type, which
affects only males, occurs most frequently. The most common treatment for X-SCID is a bone marrow
transplant, which in effect gives the patient the donor's resistance system. The Los Angeles team, headed
by bone marrow transplant specialist Dr. Kenneth Weinberg, used bone marrow from the boy's father.
The team followed up the treatment with immunosuppressive drugs to prevent rejection of the
transplanted bone marrow.
As he grew, the boy had problems with mobility. He didn't walk until he was 2 years old. He showed no
interest in running or other forms of physical activity. He fell frequently at school. His doctors attributed
the problem to the after-effects of the transplant and the immunosuppressive drugs given for it.
During a regular check-up when the boy was 12, however, Weinberg's team realized that the difficulties
with mobility arose from an entirely different cause. In addition to SCID, the boy had another disease
restricted to males: Duchenne muscular dystrophy (DMD), which also passed on through the Xchromosome from mothers to sons.
The most common and most severe form of muscular dystrophy, DMD affects about one in 4,000 males.
Caused by mutation of a gene called the dystrophin gene, it shows up as general weakening of the
muscles, starting with those in the limbs and the trunk. Most patients lose their ability to walk by the age
of 10. Few survive beyond their late twenties, commonly due to weakening muscle fibers of vital organs
such as the lungs which causing fatal pneumonia or other complications.
Intriguingly, the patient in Los Angeles had a very mild form of DMD. Once they diagnosed the disease,
Weinberg and his colleague Dr. Jan Nolta speculated whether the bone marrow transplant might have
reduced the severity of the disease by allowing normal muscle cells to have been produced from a type of
stem cell in the donor's marrow called "mesenchymal stem cells." At that point Weinberg got in touch
with Louis Kunkel, PhD, chief of the Division of Genetics at Children's Hospital Boston and professor of
This article was prepared by Stem Cell Week editors from staff and other reports.
pediatrics and genetics at Harvard Medical School. Over the past 5 years, Kunkel's group has shown that
stem cells in bone marrow transplanted into mice with DMD can restore the function of the dystrophin
gene in the mice.
Weinberg's patient offered an unexpected opportunity to check whether the same effect occurred in a
human patient with DMD. "It's a beautiful experiment of nature," Kunkel said.
The two scientific teams needed evidence that the father's cells donated in the bone marrow transplant
remained in the patient's muscle. They set out to answer the group's speculative questions: "Was it
possible that the bone marrow transplant ameliorated the symptoms of the disease? Were the transplanted
cells the reason for the mild nature of the boy's disease?" To answer these questions, a biopsy of the boy's
muscle tissue was needed. In November 2000, Weinberg's team biopsied two large muscles samples from
separate parts of the boy's body. Analysis of the samples by geneticist Emanuela Gussoni, PhD, first
author of the paper and assistant professor of pediatrics at Children's and Harvard Medical School,
showed that they did indeed contain a small number of the donated cells.
Disappointingly, subsequent analysis showed that those cells did not appear to have any effect on the
severity of the boy's DMD. "The percentage of donated cells was not sufficient to explain the patient's
clinical course," said Gussoni. However, the discovery of the donated cells in the patient's muscle tissue
13 years after the transplant indicated that bone marrow transplants may play a role in developing a
treatment based on bone marrow transplantation for patients with DMD. What the investigators did not
have was evidence of what those transplanted cells were doing at different points during the boy's growth
over the past 13 years. Gussoni set out to figure out if the transplanted cells were doing what they were
supposed to do and if they were increasing in number.
"It would have been nice to see at earlier time points whether the transplanted muscle cells were growing
throughout those years," said Gussoni. "It could be that the cells decreased or increased over time. We
cannot tell with the cells from the biopsy we took at one point in time at age 14." However, Nolta and
Gussoni were able to show that the patient still has mesenchymal stem cells in the bone marrow that had
survived in the marrow for 13 years. This finding indicates that the patient may be continuing to make
muscle cells from the original transplant.
To continue this research, the Los Angeles and Boston teams, in collaboration with Dr. Edwin Horwitz at
St. Jude's Childrens Research Hospital in Memphis, plan to give the boy a second bone marrow transplant
from his father. This will introduce more donated mesenchymal stem cells than the first transplant. The
newly transplanted cells will be biologically tagged to differentiate them from cells introduced during the
first transplant. The operation may take place by the end of this year.
"We will continue to collaborate on evaluating the tissue samples," said Weinberg. "Time will tell
whether this therapy may be effective. Our hope is that bone marrow transplantation can eventually
become a valuable therapy for patients with Duchenne muscular dystrophy and possibly other muscle
diseases." Kunkel's team is continuing to perform bone marrow transplants on mice with DMD. The
team hopes to learn more about the biological signals that send the donor cells into muscle. Weinberg's
team is studying how the immune system affects the success of the transplantation in making new muscle
cells. Together, these studies will help investigators to improve the impact of bone marrow transplants on
the disease.
Plenty of research remains to be done. But these findings hold hope for huge medical dividends. "If it
proves out," Kunkel said, "any patient with any form of muscular disease could be helped - even someone
who had muscle tissue damaged in an accident."
This article was prepared by Stem Cell Week editors from staff and other reports.